Friday, July 20, 2012

The next in our "Best of the Month" series is from February 24, 2012. To read the comments engendered by Dr. Eberhart's question, go to the original post.

I'd like to share with you this email, which I received from the illustrious Dr. Charles Eberhart this morning:

Hi Brian,

I was curious what other neuropathologists thought about
the issue of brain tumor cells transdifferentiating into endothelium and making
up significant proportions of the growing vasculature. As you may know, last
year two high profile papers stated that half or more of vascular endothelial
cells in brain tumors derived from genetically altered neoplastic cells. This
seemed inconsistent with our clinical experience, and four of us recently
published a reportexpressing our views. I would be curious to know
what other practicing surgical neuropathologists thought, and your blog might
be one forum in which to have that conversation. This is one area where I
believe that practicing pathologists have something to teach basic scientists.

Regards,

Charles Eberhart, MD PhD

Professor of Pathology, Ophthalmology and Oncology
Director of Neuropathology Chief of Ophthalmic Pathology Johns Hopkins
University School of Medicine

Please post your comments. If for some reason you are unable to
access the article through the link provided above, here is the
reference and abstract:

Microvascular proliferation is a key biological and diagnostic hallmark
of human glioblastoma, one of the most aggressive forms of human cancer.
It has recently been suggested that stem-like glioblastoma cells have
the capacity to differentiate into functional endothelial cells, and
that a significant proportion of the vascular lining in tumors has a
neoplastic origin. In principle, this finding could significantly impact
the efficacy and development of antiangiogenic therapies targeting the
vasculature. While the potential of stem-like cancer cells to form
endothelium in culture seems clear, in our clinical experience using a
variety of molecular markers, neoplastic cells do not contribute
significantly to the endothelial-lined vasculature of primary human
glioblastoma. We sought to confirm this impression by analyzing vessels
in glioblastoma previously examined using chromogenic in situ
hybridization (CISH) for EGFR and immunohistochemistry for mutant IDH1.
Vessels containing cells expressing these definitive neoplastic markers
were identified in a small fraction of tumors, but only 10% of vessel
profiles examined contained such cells and when identified these cells
comprised less than 10% of the vascular cellularity in the cross
section. Interestingly, these rare intravascular cells showing EGFR
amplification by CISH or mutant IDH1 protein by immunohistochemistry
were located in the middle or outer portions of vessel walls, but not
amongst the morphologic boundaries of the endothelial lining. To more
directly address the capacity of glioblastoma cells to contribute to the
vascular endothelium, we performed double labeling
(Immunofluorescence/FISH) for the endothelial marker CD34 and EGFR gene
locus. Although rare CD34 positive neoplastic cells unassociated with
vessels were identified (<1%), this analysis did not identify EGFR
amplified cells within vascular linings, and further supports our
observations that incorporation of glioblastoma cells into the tumor
vessels is at best extremely rare, and therefore of questionable
clinical or therapeutic significance.

Tuesday, July 10, 2012

My favorite case from the 2012 AANP Diagnostic Slide Sessionin Chicago last month featured an autopsy slide from the brain of a 25-year-old man with a
history of polysubstance abuse found unresponsive at a New Year's Eve
party. Toxicology screening was positive for methadone, lorazepam, and
cocaine. The patient died after three weeks in the intensive care unit.
Attendees were provided glass slides in advance of the session demonstrating the following findings:

Low Power: Marked white matter pallor

High Power: White matter virtually replaced by lipidized macrophages

Presenter Joshua Menke, MD of The Mayo Clinic (Rochester, MN) revealed that white matter damage was diffuse, including infratentorial structures. The subcortical U-fibers were relatively spared and myelin was disproportionately affected as compared to axons, as demonstrated in these photomicrographs from Dr. Menke's presentation:

LFB stain on left and neurofilament stain on right

Discussants included Drs. Tessa Hedley-Whyte, Craig Horbinski, Mark Cohen, and others. Before the diagnosis was revealed, Dr. Horbinski stated that he thought Delayed Hypoxic Leukoencephalopathy might be the best fit for this case. Dr. Cohen pointed out that Delayed Hypoxic Leukoencephalopathy tends spare the infratentorial regions, while the white matter damage is more diffusely distributed in toxic leukoencephalopathy. This case was ultimately revealed to be that of Toxic Spongiform Leukoencephalopathy.

Toxic leukoencephalopathy can be caused by a range of insults including radiation, chemotherapy, and drugs of abuse. Among the drugs of abuse that have been shown to cause toxic leukoencephalopathy are toluene, ethanol, cocaine, 3,4-methylenedioxy-methamphetamine, intravenous heroin, inhaled heroin pyrolysate, and psilocybin (Ref: Filley & Kleinschmidt-DeMasters NEJM 2001). Toxic spongiform leukoencephalopathy is a clinicopathologic entity first associated with the inhalation of pyrolysate heroin vapors, a practice which had its origins in Hong Kong in the 1950's and which came to be known colloquially as "chasing the dragon". Users typically "chase the dragon" by placing heroin on a creased piece of tin foil over a flame. As the drug sublimates, the user inhales the fumes. The pathophysiology of this form of leukoencephalopathy has not been clearly elucidated, but is thought to be related to a direct toxic effect of heroin on oligodendrocytes.

Monday, July 2, 2012

Here's a report from Michael Lawlor, MD, PhD summarizing the job opening updates that came out of last weekend's AANP annual meeting in Chicago. I have updated the job listings on this site to reflect Dr. Lawlor's up-to-date information:

Hi Everyone,

Dr. Mike Lawlor

As a component of the AANP Trainee Luncheon, we attempted to contact all of the institutions with job postings on the Neuropathology Blog site, and invited them to talk about their positions at the luncheon. There have been an exceptional
number of jobs filled over the past 6 months, so our roster of potential
presenters changed considerably over time.
Based on my conversations with people, here is an update on several of
the jobs currently posted on the site.

1.Brigham and Women’s Hospital: Their search for
applicants is currently closed.

2.Case Western Reserve University: Mark Cohen spoke about this position for a
few minutes, which sounds like an excellent opportunity for a research-oriented
neuropathologist that wants to spend a minority of their time on clinical
work. I would highly recommend
contacting Mark to discuss this position, if you’re in the market for a job.

3.Mayo Clinic, Stanford University, and UCSF:
These positions remain open, but these institutions are each looking for an experienced
neuropathologist who would immediately be able to take on a considerable
clinical load.

6.University of Chicago: This position remains open, and I think that
the link fell off the blog site for a short time (or I missed it). It looks like it’s back up now, and Peter
Pytel confirmed that they’re still looking for people.

7.University of Manitoba: This position remains
open, and Marc del Bigio was able to provide me with some information on
it. This information can all be found on
the link to this position, so I won’t repeat it.

8.University of Wisconsin - Madison: There had previously been two postings on the
blog site, which turned out to be two different “flavors” of descriptions for
the same job. There is one job open at
UW-Madison and they have interviewed several promising candidates, but the job
currently remains open.

9.University of Calgary- This job had previously
been posted here on the website, but it looks like it has disappeared over the
past few months. The job actually
remains open, though, and Jim Wright and Jeff Joseph sent me a lot of
information on it. It looks like the job
could involve a combination of clinical, teaching, and research
opportunities. Researchers could either
develop their own program or fit into their collaborative neuroscience
community, and preference will be given to applicants with interests in
neurodegenerative diseases, neuromuscular diseases, inflammatory diseases, or
developmental brain disorders. Jeff
Joseph also sent a beautiful picture taken from his backyard to show off some
of the scenery of Calgary, and it definitely looks like a breathtaking
area. For more information, feel free to
contact Jeff Joseph (jtjoseph@ucalgary.ca)
or Jim Wright (jim.wright@cls.ab.ca).

Two additional notes that might be
useful to people:

1. One
speaker from the pharmaceutical community mentioned that a lot of
biotech/pharmaceutical industry jobs for pathologists are actually posted on
veterinary pathology websites. If you’re
interested in pursuing such a position, you may want to widen your search to these sites.

2.I talked briefly about the NIH Loan Repayment
Program, which provides student loan repayment for projects on which the
investigator spends >50% effort on the project. These are one or two year grants, and the
submission process is very reasonable.
For anyone that has student loans, I’d encourage you to check these
awards out at their website and contact them for more details. This is a wonderful program and the people
involved in it are extremely supportive and responsive.

Good luck to everyone!

-Mike Lawlor

Thank you, Mike. And if anyone in the neuropathology community has further updates on the job listings (additions, deletions, etc.), please let me know and I'll make the necessary changes.